3.
One example of why Pharmaceutical R&D needs disruptingJonah has Sanfilippo SyndromeJonah’s mum, Jill Wood started a foundation, raises money, awareness, funds ground breakingresearch happening globally. Willing to sell her house to fund research to save Jonah.She is in a race against time – what can we do to translate ideas from bench to patient faster?How do we get more ideas tested, who funds the researchHow can we help parents and families ?

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A starting point is collaboration; software may helpHow to doit better?What can wedo withsoftware to A core root of the current inefficiencies infacilitate it ? drug discovery are due to organizations’ and individual’s barriers to collaborate effectively We have tools Bunin & Ekins DDT but need 16: 643-645, 2011 integration The future is more collaborative• Groups involved traverse the spectrum from pharma, academia, not for profit and government• More free, open technologies to enable biomedical research• Precompetitive organizations, consortia..• How can it help orphan and rare diseases?

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How CDD software has been used: BMGF 3 Academia/ Govt lab – Industry screening partnerships CDD used for data sharing / collaboration – along with cheminformatics expertise Previously supported larger groups of labs – many continued as customers More Medicines for TuberculosisCDD is a partner on a 5 year project supporting >20 labs and proving cheminformaticssupport www.mm4tb.org

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Finding Promiscuous Old Drugs for New Uses  Research published in the last six years - 34 studies - Screened libraries of FDA approved drugs against various whole cell or target assays in vitro.  1 or more compounds with a suggested new bioactivity  13 drugs were active against more than one additional disease in vitro  Perhaps screen these first?Ekins and Williams, Pharm Res 28(8):1785-91, 2011

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Finding Promiscuous Old Drugs for New Uses 109 molecules were identified by screening in vitro Statistically more hydrophobic (log P) and higher MWT than orphan- designated products with at least one marketing approval for a common disease indication or one marketing approval for a rare disease from the FDA’s rare disease research database. Created multiple structure searchable databases in CDD This work was unfunded Data for repurposing in publications is increasing but who is tracking it? FDA databases for rare disease research are XL files!! After this paper published NCGC released NPC browser….but

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Government Databases Should Come With a Health Warning Openness Can Bring Serious Quality IssuesDatabase released and within days 100’s of errors found in structures Science Translational Medicine 2011 NPC Browser http://tripod.nih.gov/npc/ Science Translational Medicine 2011 Williams and Ekins, This work was unfunded DDT, 16: 747-750 (2011)

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Need to learn from neglected disease research Do we really need to screen massive libraries of compounds as we have for TB and malaria? And groups are screening compounds already screened by others! Ekins S and Williams AJ, MedChemComm,http://www.slideshare.net/ekinssean 1: 325-330, 2010.

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Repurpose FDA drugs in silico Key databases of structures and 2D Similarity search with “hit” bioactivity data FDA drugs from screening database Export database and Suggest use for 3D searching approved with a pharmacophore drugs for testing or other model - may also indicate other uses if it is present in more than one database Suggest in silico hits for in vitro screeningEkins S, Williams AJ, Krasowski MD and Freundlich JS, Drug Disc Today, 16: 298-310, 2011

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PXR antagonist drug discovery Cancer drugs act as PXR agonists, increasing own metabolism and transport out of cells How could we block this? Preferably find a clinically used drug?

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PXR Antagonist Database Searching Screened four databases – known drugs and commercially available molecules, N = 3533 67 hits retrieved We tested in vitro a small number based on their pharmacophore fit values and mapping to the pharmacophore features Followed up hits with similarity searching using ChemSpider.com, emolecules.com Ekins et al., Mol Pharmacol, 74(3):662-72 , (2008)

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Crowdsourcing Project “Off the Shelf R&D” All pharmas have assets on shelf that reached clinic “Off the Shelf R&D” Get the crowd to help in repurposing / repositioning these assets How can software help? - Create communities to test - Provide informatics tools that are accessible to the crowd - enlarge user base - Data storage on cloud – integration with public data - Crowd becomes virtual pharma-CROs and the “customer” for enabling services

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Future Drug DiscoveryPharma R&D already looking like this – a bignetworkI think we are seeing something like this with allthe orphan disease networks tooMassive collaboration networks – softwareenabled. We are in “Generation App”Crowdsourcing will have a role in R&D. Drugdiscovery possible by anyone with “app access” Ekins & Williams, Pharm Res, 27: 393-395, 2010.

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Found on the internet http://dl.dropbox.com/u/14511423/VRU.pptx The Evolving Pfizer R&D Ecosystem Evolving paradigm for the discovery of medicines (Collaborative)  A vision that points towards open innovation and collaborations  Open research model to collectively share scientific expertise Enhance speed of drug discovery beyond individual resource capabilities (Speed)  Limited research budgets and capabilities driving greater shared resources  Goal to see all partners succeed by accelerating the SCIENCE  Synergize Pfizer’s strengths with Research Partners (Knowledge)  Pair Pfizer’s design, cutting edge tools, synthetic excellence with research partners (academics, not-for-profits, venture capitalists, or biotechs) to develop break through science, novel targets, and indications of unmet medical need  Current example of academic and not-for-profits partners (Discover and Publish)  Drive to publish in top journal with science receiving high visibility and interest Body clock mouse study suggests new drug potential Mon, Aug 23 2010 By Kate Kelland LONDON (Reuters) - Scientists have used experimental drugs being developed by Pfizer to reset and restart the body clock of mice in a lab and say their work may offer clues on a range of human disorders, from jetlag to bipolar disorder. a few months ago we entered into a collaboration with the giant pharmaceutical industry Pfizer to test some of their leading molecules for potential relevance to HD.Contacts:  Travis Wager (travis.t.wager@pfizer.com)  Paul Galatsis (paul.galatsis@pfizer.com)

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The newest drug discovery realityGone full circlePharma now becoming more like rare disease groupsWorking on a shoestring, limited resources, leverages academics,partners with disease foundations, funded by them – open innovationCollaboration is a core elementIf Jill Wood or others can become a virtual pharma, if they have enoughdomain knowledge and drivePfizer and other pharmas can be more like Jill, smaller, leaner, workingon many more diseases as collaboratorsIn silico approaches and collaboration = central to rare disease drugdiscovery